The development of antibiotic-resistant bacteria is a prevalent concern that has prompted the development of new antimicrobial agents (Park, et al., International Journal of Molecular Sciences 2011, 12, 5971; Laverty, et al., International Journal of Molecular Sciences 2011, 12, 6566; Tew, et al., Accounts of Chemical Research 2010, 43, 30; Boucher, et al., Clinical Infectious Diseases 2009, 48, 1). As an alternative to conventional antibiotics, antimicrobial peptides (AMPs) have received widespread attention. Many of the naturally occurring AMPs elicit antibacterial activity by targeting the cellular membrane (Park, et al., International Journal of Molecular Sciences 2011, 12, 5971; Laverty, et al., International Journal of Molecular Sciences 2011, 12, 6566; Tew, et al., Accounts of Chemical Research 2010, 43, 30). Although these peptides have diverse primary structures, many exhibit a net cationic charge and facially amphiphilic secondary structure in which hydrophobic and hydrophilic domains exist on opposite ‘faces’ of the molecule (Zhao, Y. Current Opinion in Colloid & Interface Science 2007, 12, 92); it is the cationic, amphiphilic character that appears to give rise to AMPs' unique mechanism of action (Park, et al., International Journal of Molecular Sciences 2011, 12, 5971; Laverty, et al., International Journal of Molecular Sciences 2011, 12, 6566; Tew, et al., Accounts of Chemical Research 2010, 43, 30). These AMPs first interact with negatively charged bacterial membranes via electrostatic bonding (Laverty, G.; Gorman, S. P.; Gilmore, B. F. International Journal of Molecular Sciences 2011, 12, 6566; Brogden, K. A. Nature Reviews Microbiology 2005, 3, 238). After the initial interaction, AMPs' hydrophobic domains interact with the hydrophobic membrane interior, ultimately disrupting the membrane and resulting in cell death (Laverty, G.; Gorman, S. P.; Gilmore, B. F. International Journal of Molecular Sciences 2011, 12, 6566; Brogden, K. A. Nature Reviews Microbiology 2005, 3, 238). Owing to their membrane-targeting activity, AMPs exhibit reduced instances of bacterial resistance and are promising antibiotic alternatives (Laverty, G.; Gorman, S. P.; Gilmore, B. F. International Journal of Molecular Sciences 2011, 12, 6566; Grenier, et al., Bioorganic & Medicinal Chemistry Letters 2012, 22, 4055; Ling, et al., Nature 2015, advance online publication). However, high production costs and scalability difficulties, as well as low solubility, bioavailability and metabolic stability (e.g., instability in the presence of proteases), has limited their clinical application (Tew, et al., Accounts of Chemical Research 2010, 43, 30; Scorciapino, et al., Biophys. J. 2012, 102, 1039; Hancock, R. E. W.; Sahl, H.-G. Nature Biotechnology 2006, 24, 1551).
Accordingly, there is a need for new agents that have antibacterial properties.